Oral Therapy for Colorectal Cancer: How to Choose

Introduction

Colorectal cancer is the fourth most common malignancy diagnosed in the United States and the second most common cause of cancer death. For several decades, fluorouracil(Drug information on fluorouracil) (5-FU) stood alone as the only agent with clinical activity against colorectal cancer. Even with the introduction of irinotecan(Drug information on irinotecan) (Camptosar) and oxaliplatin(Drug information on oxaliplatin), 5-FU remains a component of standard adjuvant therapy and the initial management of metastatic disease.

Because of its incomplete and erratic oral bioavailability, 5-FU is commonly administered intravenously.[1] However, patients prefer oral rather than intravenous therapy,[2] with oral treatment potentially more convenient and less costly. Thus, methods to effectively deliver fluorinated pyrimidines orally have recently been developed.

Two general approaches have been undertaken. The first involves the use of prodrugs that are absorbed intact in the gastrointestinal tract and are ultimately converted to 5-FU in normal or tumor tissues. Examples of this method of oral administration are capecitabine(Drug information on capecitabine) (Xeloda) and tegafur(Drug information on tegafur), a component of UFT and S-1 (Figure 1).

An alternate approach of delivering 5-FU by the oral route is to block its gastrointestinal degradation via coadministration of an inhibitor of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme in 5-FU catabolism. Inhibitors of DPD in clinical development include eniluracil; uracil, a component of UFT; and 5-chloro-2,4-dihydroxypyridine (CDHP), a component of S-1 (Figure 1).

Preclinical models suggest an improved therapeutic index with administration of oral fluoropyrimidines. This observation has fueled rapid clinical development of these agents over the past 5 years.

Fluorouracil

Heidelberger et al first synthesized 5-FU in 1957, designing a pyrimidine antimetabolite that also inhibits thymidylate synthase (TS).[3] Following intravenous administration, 5-FU undergoes both anabolism and catabolism (Figure 2). Within minutes, 80% of the drug is catabolized to the inactive dihydro-5-FU. This conversion is mediated by dihydropyrimidine dehydrogenase (DPD), an enzyme found predominantly in the liver but widely present in other human tissues. The remaining 20% of 5-FU is anabolized to the active species responsible for cytotoxicity.[4] Figure 2 shows the steps in the formation of the cytotoxic metabolites of 5-FU.

Mechanisms of Action

Three distinct mechanisms of action of 5-FU have been described.[5] Fluorouracil is converted to fluorodeoxyuridine (FUdR) by thymidine phosphorylase. Fluorodeoxyuridine is then phosphorylated by thymidine kinase to fluorodeoxyuridine monophosphate (FdUMP). Fluorodeoxyuridine monophosphate forms a stable covalent complex with TS in the presence of the reduced folate cofactor, 5,10-methylenetetrahydrofolate. This inhibition of TS prevents the formation of deoxythymidine monophosphate (dTMP) from deoxyuridine monophosphate (dUMP) and thereby decreases the availability of deoxythymidine triphosphate (dTTP) for DNA replication and repair.

In addition to decreasing the availability of dTTP, the inhibition of TS causes an increase in the amount of dUMP available in the cell. Deoxyuridine monophosphate, like FdUMP, can be anabolized to the triphosphate level. Fluorodeoxyuridine triphosphate (FdUTP) and deoxyuridine triphosphate (dUTP) can be incorporated into DNA, contributing to the inhibition of DNA elongation and altering DNA chain stability.

Furthermore, fluorouridine monophosphate (FUMP) is formed from 5-FU by either the sequential actions of uridine phosphorylase and uridine kinase, or the direct action of orotate phosphoribosyltransferase (OPRT) in the presence of phosphoribosylpyrophosphate (PRPP). Subsequently, FUMP is phosphorylated to form fluorouridine diphosphate (FUDP) and then fluorouridine triphosphate (FUTP). The triphosphate is incorporated into nuclear and cytoplasmic RNA, thereby interfering with normal RNA processing and function.

Biochemical Modulation

Fluorouracil has been investigated extensively in the treatment of colorectal malignancies. However, response rates to 5-FU alone rarely exceed 20%. Attempts to improve the efficacy of 5-FU without increasing morbidity have included the addition of biochemical modulators and alterations in administration schedules.[6]

The most successful example of biochemical modulation of 5-FU is the addition of reduced folates in the form of leucovorin to stabilize the ternary complex of FdUMP and TS. A meta-analysis of trials comparing 5-FU alone to 5-FU plus leucovorin found an improved response rate in patients with metastatic colorectal carcinoma treated with the combination (11% vs 23%; P < 10^-7).[7] However, there was no impact on overall survival; median survival in patients treated with 5-FU alone was 11 months, compared with 11.5 months in those given 5-FU plus leucovorin.

Many administration schedules of 5-FU have been tested. They differ in patterns of toxicity; however, none of these regimens has demonstrated a major survival advantage.

A recent meta-analysis compared bolus 5-FU (with or without leucovorin) to protracted venous infusions of 5-FU in patients with metastatic colorectal cancer.[8] This analysis, which combined six clinical trials involving 1,219 patients, found an overall response rate of 22% in the patients who received continuous-infusion 5-FU, as opposed to a rate of 14% in patients treated with bolus 5-FU. Patterns of toxicity differed, with severe hematologic toxicity more common with bolus treatment, and hand-foot syndrome more common with infusional therapy.[9] However, there was only a minimal difference in median survival (12.1 months with bolus treatment vs 11.3 months with infusional therapy; P = .04).

Rationale for Developing Oral Agents

In a survey study of cancer patients,[2] Liu et al found that patients prefer oral rather than intravenous treatment, but are unwilling to sacrifice tumor response for ease of administration. In this study of 103 patients, 89% stated a preference for oral therapy. Reasons for this choice included convenience and fewer problems with venous access. Nevertheless, 70% of survey respondents were unwilling to accept a lower response rate with oral therapy. Thus, although convenience is an important potential advantage, therapeutic equivalence or superiority is required of oral agents.

Daily oral therapy also has the potential to mimic the pharmacology of protracted intravenous infusions of 5-FU, without the cost, complications, and inconvenience of ambulatory infusion pumps. Given some evidence of an improved therapeutic index for protracted infusion schedules in colorectal cancer,[8-11] the recent clinical development of oral fluoropyrimidines has focused on continuous daily schedules.

New Target for 5-FU Biochemical Modulation: Catabolism

Traditionally, efforts at biochemical modulation of 5-FU activity have focused on anabolic pathways. The most successful example of this approach is the use of leucovorin to improve the inhibition of TS by FdUMP.

Recently, however, the role of 5-FU catabolism in toxicity and resistance was recognized. This led to the identification of a new target for biochemical modulation, namely, the enzyme DPD. This rate-limiting enzyme in 5-FU catabolism accounts for 5-FU’s serum half-life of approximately 15 minutes.

In patients with a congenital deficiency of DPD, treatment with standard doses of 5-FU results in severe and life-threatening toxicity associated with prolonged half-life and renal excretion.[12] Intestinal expression of DPD accounts for the poor oral bioavailability of 5-FU. In animal models, the 5-FU catabolite dihydrofluorouracil has been associated with toxicity and tumor resistance.[13,14] Furthermore, DPD levels in human tumor tissue have been correlated with clinical resistance to 5-FU.[15]

These observations led to the development of DPD inhibitors as biochemical modulators of 5-FU in the hope that inhibition of DPD would permit effective oral administration of 5-FU with an improved therapeutic index compared to intravenous treatment.